Portal hypertension occurring without cirrhosis is an unusual condition. It is also a broad topic which encompasses a number of different diseases, each of which is even more unusual. The management for each of these diseases is often very different. Non-cirrhotic portal hypertension (NCPH) can be divided into three broad categories depending on the anatomic origin of the portal hypertension, namely pre-hepatic, hepatic, and post-hepatic. Within hepatic causes of NCPH nodular regenerative hyperplasia (NRH) is relatively rare and most knowledge on the topic has derived from case reports and series. There has been limited systematic research. It has become apparent, initially through the consult service of the Liver Diseases Branch, that there are a number of patient cohorts followed at the Clinical Center of the National Institutes of Health (NIH) who are at risk for NRH and NCPH. A more systematic approach has been instituted to evaluate these patients. The first cohort to be evaluated (in a retrospective manner) was patients with Chronic Granulomatous Disease (CGD). This is in collaboration with Drs. Holland and Malech of the National Institute of Allergy and Infectious Diseases. CGD is a genetic disorder affecting the neutrophil oxidative burst, which in turn impedes killing of certain pathogens. In the CGD protocol 194 patients have been previously enrolled. All available clinical information was reviewed with the intention of a comprehensive evaluation of hepatic abnormalities. The initial focus was to define the hepatic findings in this cohort, as little hepatic pathology other than liver abscess, hepatic granulomata, and lobular hepatits had been described. Liver enzyme elevations were common, occurring in 73% of patients during a mean of 8.9 years follow up. ALP elevations were seen in 25% of patients. Drug toxicity was more common than previously appreciated, being documented in 15% of patients, however it was considered likely to occur more frequently than documented. Hepatomegaly and splenomegaly were common, occurring in more than a third and greater than half of patients respectively. Granulomata were found in 75% and lobular hepatitis in 90% of liver biopsies. Portal venopathy was common (80%) and was associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of liver abscess episodes. NRH was seen in 9 patients. Venopathy and NRH are known causes of NCPH. The direction of the evaluation then shifted. The question asked was how do these findings impact on clinical outcome? A model was developed for mortality with an emphasis on the hepatic findings. Twenty four patients had died, all of infectious complications. By Cox regression analysis three factors were associated with mortality. They were: decreases in platelet count (>9,000/l per year; HR 4.7, p=0.007), alkaline phosphatase elevations (>0.25 per year; HR 4.5, p=0.01) and history of liver abscess (HR 3.1, p=0.03). Multivariable logistic regression showed decreasing platelet count was associated with splenomegaly, elevated IgG and increasing number of ALT elevations; greater number of alkaline phosphatase elevations and abscess were both associated with increasing age and number of infections. Prospective evaluation revealed elevated hepatic-venous pressure gradients in two patients with progressive thrombocytopenia, suggestive of portal hypertension. These data suggest mortality in patients with CGD is associated with the development of NCPH, likely due to injury to the microvasculature of the liver from repeated systemic and hepatic infections. The slope of decline in platelet count may be a useful measure of progression of portal hypertension over time. A second cohort of patients we have found to be at risk for NCPH and NRH is patients with sickle cell disease (SCD). This is in collaboration with Drs Gladwin and Kato of the National Heart Lung and Blood Institute. SCD is a multi-system disorder leading to progressive organ damage. Although hepatic abnormalities have been described in SCD, the impact of hepatic involvement on disease outcome is unknown. The aim of this study was to determine if markers of liver involvement affect survival in SCD. A large cohort of well-characterized patients with SCD followed at the NIH, were prospectively evaluated. Cox proportional hazards regression was used to assess factors associated with mortality. Univariate and multivariable logistic regression were performed to determine factors associated with identified predictors of mortality. A total of 247 patients (148F/99M) with a mean age of 36.2 (18-74) years were followed for a median of 26.7 (0.3-49) months. Twenty-two patients died, predominantly of septic complications or sudden cardiopulmonary arrest. One patient with hepatitis C infection and iron overload underwent liver transplantation. Liver parameters, markers of iron overload and factors previously identified to be associated with mortality in SCD (age, pulmonary hypertension, WBC and creatinine) were evaluated by Cox regression. By multivariable analysis, direct bilirubin (HR 2.6 95% CI 1.4-4.8, p=0.002) and log ferritin (HR 1.6 95% CI 1.1-2.5, p=0.018) were independently associated with mortality. Pulmonary hypertension and WBC contributed to the final mortality model but were not independently statistically significant. To determine factors associated with predictors of mortality, logistic regression was performed. By multivariable analysis, increasing number of blood transfusions, WBC and ALT were associated with a serum ferritin above 1,000 g/l while increasing inferior vena cava diameter, mean arterial blood pressure, AST and LDH were associated with an elevation of direct bilirubin. These results were understood to imply that serum ferritin and direct bilirubin are independently associated with mortality in SCD. Although ferritin reflects transfusion-related iron overload, it may also be a marker of liver inflammation. Elevation of direct bilirubin is associated with hepatic congestion and markers of hemolysis. The inability to handle increased bilirubin loads in the face of chronic congestion may indicate subtle but clinically important impairment of hepatic synthetic function. As a second phase of this study we are now systematically evaluating patients in this cohort who have hepatic abnormalities to determine the exact nature of hepatic involvement and the incidence of NCPH and NRH in SCD. Although neither CGD nor SCD is a primary liver disease it appears that liver disease as a result of the underlying systemic disease impacts mortality in both cases. Of interest is that it is NCPH and more specifically NRH that seem to be the predominant liver lesion. CGD and SCD may serve as a model for the development of NCPH and elucidating the biology of NRH. To further understand the biology of NRH a study of liver biopsies has been undertaken with Dr. Reshamwala of the University of Maryland and Dr Kleiner of the National Cancer Institute. In this study liver biopsies from CGD and SCD patients (and patients with other systemic diseases) with and without NRH have been evaluated and correlated with laboratory and clinical findings. This is in an effort to delineate the clinical spectrum of, and to carefully define NRH. There is one other form of NCPH that is being studied. Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disorder associated with polycystic renal disease. It is typically associated with varices and variceal bleeding is a common cause of death. The renal involvement may be significant and patients may require renal replacement therapy. The aim of this study is to prospectively define the natural history of the syndrome and to better understand the pathogenesis. This is in collaboration with Drs. Gunay-Aygun and Gahl of NIHG